This invention provides a process for encapsulating a polar organic solvent which comprises subjecting one or more C1-12 alkyl acrylates or C1-12 alkyl methacrylates to living polymerization in the presence of the polar solvent.
Polymeric capsules and hollow particles can be prepared both from monomeric starting materials as well as from oligomers and pre-formed polymers. (Arshady, R., Microspheres, Microcapsules Liposomes 1999, 1, 1461-1732). In most cases, the process involves a disperse oil phase in an aqueous continuous phase, and the precipitation of polymeric material at the oil-water interface causing each oil droplet to be enclosed within a polymeric shell. Interfacial polycondensation is used to prepare poly(urea) (Beestman, G. B., et. al., U.S. Pat. No. 4,417,916, Nov. 29, 1983), poly(amide), or poly(ester) capsules (Arshady, R. J., Microencapsulation 1989, Vol. 6, No. 1, 13-28), for instance, by reaction between an oil soluble monomer and a water soluble monomer at the oil-water interface. On the other hand, vinyl polymers such as poly(styrene), acrylates and methacrylates prepared by free radical polymerization under suspension (Kasai et. al., U.S. Pat. No. 4,908,271 (Mar. 13, 1990)) or emulsion polymerization (McDonald et. al., U.S. Pat. No. 4,973,670 (Nov. 27, 1990)), (McDonald, C. J. et. al., Macromolecules 2000, 33, 1593-1605) conditions have been used to prepare hollow or capsular polymer particles. In this approach, the dispersed oil phase usually serves as the polymerization solvent. The oil phase is chosen so as to be a good solvent for the monomeric starting materials but a non-solvent for the product polymer. Therefore, upon polymerization the system is comprised of three mutually immiscible phases. Over the past three decades, several groups have studied the factors governing the morphologies that two immiscible phases can adopt when they are brought together in a third immiscible phase by means of a velocity gradient or otherwise. Their findings have led to an understanding of the morphologies that result when, for instance, two immiscible polymers are brought together in a non-solvent for either. This occurs in a seeded emulsion polymerization when the formed polymer and seed polymer are in mutual contact, and are dispersed in an aqueous phase. The same fundamental principles govern the morphology of composite particles that result when a polymer, and a non-solvent organic oil are brought together in an aqueous dispersion, as is the case during the encapsulation of an organic oil.
Torza and Mason (Torza, S. et. al., Journal of Colloid and Interface Science 1970, Vol. 33, No. 1, 67) studied the phase behavior of low viscosity, immiscible organic liquids dispersed in an aqueous phase as the drops were subjected to varying shear and electric fields. They defined the spreading coefficient, Si=xcex3jkxe2x88x92(xcex3ij+xcex3ik), where i, j, and k represent the three immiscible phases and xcex3, the interfacial surface tension. For the premise that, xcex312 greater than xcex323, it follows that S1 less than 0. The definition of Si, leads to only three possible sets of values of Si:
S1 less than 0, S2 less than 0, S3 greater than 0;xe2x80x83xe2x80x83[1]
xe2x80x83S1 less than 0, S2 less than 0, S3 less than 0;xe2x80x83xe2x80x83[2]
S1 less than 0, S2 greater than 0, S3 greater than 0;xe2x80x83xe2x80x83[3]
It was shown that for interfacial conditions of equation [1] the core-shell morphology is preferred, while for equation [2] the hemispherical morphology is preferred. Good agreement was found between the theoretical predictions and experimental results. It is noteworthy, that Torza and Mason used low viscosity oils that are able to diffuse rapidly and assume the lowest interfacial energy morphology within the time frame of the experiment. Hence, their results may not extend to cases when one or more of the components is a high molecular weight polymer, since diffusional resistance may prevent equilibrium morphology from being realized during the experimental time frame.
Sundberg et. al. (Sundberg, D. C. et. al., Journal of Applied Polymer Science 1990, 41, 1425) published a theoretical model based on the Gibbs free energy change of the process of morphology development. Starting with three immiscible phases; oil, polymer and water, they showed that the Gibbs free energy change per unit area for the process leading to a core shell morphology (with oil encapsulated within the polymer phase), is given by:
xcex94G=xcex3op+xcex3pw(1xe2x88x92xcfx86p)xe2x88x922/3xe2x88x92xcex3owxe2x80x83xe2x80x83[4]
Where xcex3op, xcex3pw, and xcex3ow are the oil-polymer, polymer-water and oil-water interfacial tensions and xcfx86p is the volume fraction of the polymer (in polymer plus oil xe2x80x9ccombined phasexe2x80x9d). In the limit as xcfx86p tends to zero, equation [4] reduces to,
xe2x80x83xcex94G=(xcex3op+xcex3pw)xe2x88x92xcex3owxe2x80x83xe2x80x83[5]
Thus, when xcex3ow greater than (xcex3op+xcex3pw) [6], the core shell morphology with the core oil being engulfed by the polymer is the thermodynamically stable morphology. Analogous expressions were derived for the hemispherical, inverse core shell and distinct particle morphologies. Using these expressions the authors were able to predict the expected morphologies for a given set of interfacial conditions. The predictions were checked and confirmed by experiment.
In an earlier work, Berg et. al. (Berg, J. et. al., Microencapsulation 1989, Vol. 6, No. 3, 327) showed the above analysis is equally valid when the polymer is synthesized in situ by free radical polymerization. Poly(methyl methacrylate) was prepared via free radical polymerization by dispersing n-decane or hexadecane, methyl methacrylate and an oil soluble initiator in water containing a surfactant or stabilizer. It was shown that the resultant morphology was critically dependent on the type of emulsifier used. The authors concluded that this observation appeared to be related to the minimization of interfacial energy for the particles as they are dispersed in water. Thus, the particle morphology that results from in situ polymer synthesis in suspension/emulsion polymerization conditions is predominantly driven by interfacial energy criteria. It must be stated that the above model assumes thermodynamic equilibrium and therefore predicts xe2x80x9cfinalxe2x80x9d equilibrium particle morphology. The fact that it correctly predicts the particle morphology when polymer is synthesized in situ implies that phase separation kinetics competes favorably with polymerization kinetics (under the experimental conditions used by Berg et. al.).
The work of the four major research groups in the area, i.e., Kasai et. al., Okubo et. al., McDonald et. al., and Sundberg et. al., shows that present techniques allow only the encapsulation of relatively hydrophobic solvents. McDonald et. al. and Sundberg et. al. have encapsulated highly non-polar core oils such as decane and octane. McDonald et. al. (McDonald, C. J. et. al., Macromolecules 2000, 33, 1593-1605), (McDonald et. al., U.S. Pat. No. 4,973,610, Nov. 27, 1990) have also reported the preparation of hollow latex particles by conventional and seeded emulsion polymerization. The conventional emulsion system consisted of an oil phase dispersed in water with the aid of surfactant. The oil phase contained monomer that is essentially non-water soluble and a hydrocarbon oil that dissolves the monomer but is non-solvent for the formed polymer. The aqueous phase consisted of a water soluble initiator and a water miscible alcohol.
The seeded emulsion polymerization differed from the above system in that the seed latex particles were swollen by the oil phase prior to initiation of the polymerization. The encapsulation process occurred in two stages. First, a low molecular weight polymer was made (e.g., 8000 Da using chain transfer agents). The polymer being insoluble in the hydrocarbon solvent begins to phase separate and concentrate at the oil water interface. At this point, a second charge of crosslinker and monomer were added to the system. The additional monomer and crosslinker absorb into the surface polymer phase on the oil droplets. Oligomers from initiation in the water phase also anchor onto this surface polymer phase. Thus, the surface polymer layer (on the oil droplets) now serves as the locus of further polymerization and the crosslinked network that stabilizes the surface polymer layer yielding the hollow particle morphology.
The addition of water miscible alcohol to the water phase was shown to be critical for efficient encapsulation; in the absence of alcohol, latex particles with a layer of hydrocarbon on the surface were obtained. In a model experiment, increasing the amount of alcohol lowered the interfacial surface tension between an alcoholic aqueous phase and an 80/20 mixture of poly(styrene) and ethylbenzene, thereby partially explaining the enhanced encapsulation efficiency in the presence of alcohol.
Kasai et. al. and Okubo et. al. have encapsulated slightly more polar materials such as benzene, toluene and xylene. Kasai et al., (Kasai et al., U.S. Pat. No. 4,908,271 (Mar. 13,1990)), (Kasai et al., U.S. Pat. No. 4,798,691 (Jan. 17, 1989)) have described the production of hollow polymer particles by both classical suspension and emulsion polymerizations, and seeded suspension polymerization. In the classical suspension polymerization method, the oil phase consisted of an inert solvent, a hydrophobic and a hydrophilic monomer, a crosslinking monomer and an oil soluble free radical initiator. The suspension was stabilized with organic or inorganic stabilizers. This method yielded hollow polymer particles with a mean size distribution of about 10 microns and a total monomer conversion of 98%. It was shown that exclusion of the hydrophilic monomer from the system yielded porous polymer particles rather than hollow particles. Also, exclusion of the crosslinking monomer led to solid particles with no core-shell structure. Therefore, to obtain the capsular morphology it is necessary that the formed polymer has both hydrophobic and hydrophilic content and be crosslinked.
A plausible mechanism supported by their results is as follows. Upon thermal initiation the suspension polymerization yields terpolymers comprised of the hydrophobic, hydrophilic and crosslinking monomers. Since, the hydrophilic monomer partitions into the water phase in suspension polymerization conditions, the early part of the suspension polymerization would essentially produce copolymer that is rich in the hydrophobic monomer and the crosslinking monomer (divinyl benzene (DVB), also hydrophobic). On the other hand, the latter part of the polymerization would yield terpolymers rich in the hydrophilic monomer. Since the reactivity of the second vinyl group on DVB is lower than that of the first, it is postulated that the copolymers formed during the early part of the suspension polymerization will possess unreacted vinyl groups that will remain available for polymerization until the latter part of the suspension polymerization. Hence, the terpolymers polymers formed in the early and late periods of the suspension polymerization will be covalently bonded to yield amphiphilic gels. These amphiphilic gels would migrate to the oil water interface and precipitate as the crosslinking reaction proceeds, thereby yielding the core-shell morphology.
This hypothetical mechanism partly explains why the presence of crosslinker is critical to obtaining the core-shell morphology. Or another plausible reason is based on the fact that, in general, polymer precipitation at an interface is associated with an entropic penalty. This is so because of the reduced degrees of freedom available to polymer at an interface as opposed to polymer in the bulk phase. This entropic penalty is less significant for crosslinked polymer than it is for linear polymer because the former has fewer degrees of freedom to start with. Therefore, crosslinked polymer is more likely to precipitate at an interface than is linear polymer (other parameters being identical).
In summary, the entropic advantage of crosslinked polymer for precipitation at an interface as well as the formation of amphiphilic gels in the presence of crosslinker may explain the fact that core-shell particles are obtained only when the forming polymer is crosslinked.
Particles of sub-micron diameter were achieved using the emulsion polymerization method. Here, water soluble initiator and a surfactant were employed with the remainder of the system being essentially the same as described above. Like the suspension system, the presence of both hydrophilic and crosslinking monomer was critical to obtaining hollow particles.
Seeded suspension polymerization involved the use of fine non-crosslinked latex particles prepared via emulsion polymerization in a previous step. It was essential that low molecular weight polymer (7000-10,000 Da) be used to ensure efficient swelling of the seed particles. The size and polydispersity of the final hollow polymer particles were controlled via the seed particles. Using this method sub-micron to 10 micron monodisperse particles were prepared. These hollow particles were monodisperse in comparison to those prepared via suspension polymerization.
In both the emulsion and seeded suspension polymerization methods, the presence of both hydrophilic and crosslinking monomer was critical to obtaining hollow particles.
The compositions used in the examples were based on:
Styrene, n-butyl acrylate or butadiene as hydrophobic monomer;
4-vinyl pyridine, methyl methacrylate, methacrylic acid or hydroxyethyl methacrylate as hydrophilic monomer;
Divinyl benzene as crosslinking monomer: and
Toluene or benzene as oil phase.
Okubo et. al. (Okubo, M. et. al., Macromol. Symp. 1996, 101, 509-516) prepared core-shell poly(divinylbenzene) (PDVB) particles (xcx9c10 xcexcm diameter) containing toluene in the core and PDVB in the shell by seeded suspension polymerization. Polystyrene seeds (xcx9c3 xcexcm diameter) were swollen with DVB and toluene using the xe2x80x9cDynamic Swelling Methodxe2x80x9d (DSM) that Okubo developed earlier (Okubo, M. et. al., Colloid Polym. Sci. 1991, 269, 222-226) for the preparation of monodisperse homogeneous PDVB particles. In DSM, seed latex particles are dispersed in a solution of toluene, DVB, radical initiator (such as benzoyl peroxide) and stabilizer in an ethanol/water mixture. Slow addition of more water to this mixture drives toluene, DVB and the radical initiator into the seed particles since the water/ethanol binary solvent becomes increasingly polar and therefore immiscible with these organic compounds. In contrast with the conventional swelling method, this represents an additional force that drives solvent, monomer and initiator into the seed particles. In the conventional swelling method, the seed particles, solvent, monomer and initiator are soluble in the alcohol/water mixture that serves as the polymerization medium. Hence, the only driving force for the solvent, monomer and initiator to partition into the seed particles is the gain in entropy resulting from mixing of these compounds with the seed polymer. There is therefore an upper limit to the amount of solvent, monomer and initiator that will swell the seeds since the gain in entropy associated with the mixing process becomes insignificant after some finite degree of swelling. Consequently, using the conventional swelling method, xcx9c2 xcexcm seed particles can be swollen to xcx9c5 xcexcm diameter. Using DSM, on the other hand, xcx9c2 xcexcm seed particles can give up to xcx9c10 xcexcm swollen particles. Following the swelling process using DSM, thermal polymerization of the DVB monomer yields core shell particles with toluene in the core and a PDVB shell.
Okubo et. al. (Okubo, M. et. al., Colloid Polym. Sci. 1997, 275, 992-997) have shown that polymerization of styrene under the same seeded polymerization conditions does not yield hollow particles, i.e., only when the formed polymer is crosslinked does it precipitate at the interface with water yielding the core-shell morphology. By observing the evolution of the particle morphology during the course of the suspension polymerization, they proposed a mechanism for the formation of the hollow particles: the formed PDVB precipitates in the swollen seed particles and is trapped near the interface based on surface coagulation and gradually piles up at the inner surface, resulting in a cross-linked PDVB shell.
Okubo et. al. (Okubo, M. et. al., Colloid Polym. Sci. 1998, 276, 638-642) have also shown that a minimum amount of seed polymer of a minimum molecular weight is necessary for the formation of the core-shell structure. The core volume is controllable via the amount and nature of the core solvent (Okubo, M. et. al., Colloid Polym. Sci. 1996, 274, 433-438). Increasing the amount of core solvent for a given amount of seed particles increased the core size. Also, using core solvents that differ in their water solubility, it was shown that solvents with higher water solubility gave smaller particles with smaller core volume due to loss of core solvent to the alcohol/water polymerization medium. Okubo et. al. (Okubo, M. et. al., Colloid Polym. Sci. 2000, 278, 659-664) conducted suspension polymerizations of DVB in xylene/toluene solutions of polymers differing in their polarity (as reflected by the solubility parameter) (Table 1), and monitored particle morphology. The polymer solutions in these experiments represented seed polymer of seeded suspension polymerizations. The interfacial tension between water and the polymer solutions determined the observed particle morphology.
The interfacial tension between water and xylene/toluene (1/1, w/w) is 34.8 mN/m and that between water and a 0.01 wt % PDVB solution in xylene/toluene (1/1, w/w) is 29.5 mN/m. It was observed that when the interfacial tension between water and the seed polymer solution was below 20 mN/m, no hollow particles formed. For interfacial tension between 20-30 mN/m, hollow particles with a rough inner (shell) surface and an unclear shell structure were observed. Clear hollow particles were observed only when the interfacial tensions were above 30 mN/m. Thus, hollow particles formed only when the PDVB interfacial surface tension with water is below that of the core polymer solution.
Since these groups set out to synthesize hollow polymer particles, the nature of the core oil has not been relevant. However, if core-shell particles are intended for encapsulation of the core material, then it becomes desirable that the technique allows encapsulation of both hydrophobic and hydrophilic core materials.
Core-shell particles, with polymer engulfing an oil core, only form if the sum of the oil/polymer and polymer/water interfacial tensions is less than the oil/water interfacial tension. Consequently, encapsulation of more hydrophilic material demands the ability to synthesize sufficiently amphiphilic polymers that will satisfy this interfacial requirement. Copolymers comprised of an oil-soluble and a water-soluble monomer are amphiphilic materials whose polarity characteristics can be conveniently controlled by varying the comonomer ratios. However, the synthesis of these materials in suspension polymerization conditions is significant since the water-soluble monomer partitions into the aqueous phase and is only partially incorporated into polymer forming in the oil phase if conventional free radical polymerization is used as the means of polymer synthesis. Thus, current techniques that use conventional free radical polymerization as the means of polymer synthesis do not permit the in situ synthesis of such amphiphilic polymers in suspension or emulsion polymerization conditions. Applicants propose that the use of a living polymerization method as the means of polymer synthesis will allow the preparation of amphiphilic copolymers by suspension polymerization and henceforth, meet the interfacial requirement for encapsulating more hydrophilic core oils.
According to one aspect of the present invention, there is provided a process for encapsulating a polar organic solvent which comprises subjecting one or more C1-12 alkyl acrylates or C1-12 alkyl methacrylates to living polymerization in the presence of the polar solvent.
According to another aspect of the present invention, there is provided a process for encapsulating a polar organic solvent comprising: synthesis of an amphiphilic co-polymer by controlled/living polymerization in a polar solvent; carrying out the synthesis until a predetermined degree of conversion or length of the co-polymer chain is obtained; addition of a crosslinking monomer to form a reaction mixture; and subjecting the reaction mixture to mixing to yield microcapsules containing the polar solvent.
According to still another aspect of the present invention, there is provided a microcapsule comprising a polar solvent encapsulated by an amphiphilic co-polymer shell.
The process described herein relies on the use of controlled/living polymerization to incorporate substantially all monomer into the capsule wall. The encapsulation system of the present invention depends upon forming a crosslinked polymer that has a surface energy, or polarity, higher than that of the organic phase, but lower than that of the aqueous phase. In this way, the polymer capsule wall forms at the location of lowest energy, i.e. at the interface between the organic and the aqueous phase. In the heterogeneous polymerization system described herein, a significant part of the hydrophilic monomer partitions into the aqueous phase. As the polymer wall forms on the organic side of the interface, the organic phase becomes depleted of this hydrophilic monomer. Living polymerizations allow the individual polymer chains to remain active long enough to permit the portion of the hydrophilic monomer present in the aqueous phase, to partition back into the organic phase, thereby becoming incorporated into the forming polymer.
Living/controlled polymerizations are characterized by maintaining their active polymer chain ends for an extended period of time, sufficient to convert substantially all available monomer into polymer. The presence of an aqueous phase in the polymerization systems as described herein precludes the use of living anionic and living cationic polymerizations, as their reactive polymer chain ends, a carbanion or carbocation, respectively, would be instantly quenched by the water. There are three major living radical polymerizations presently known, called Atom Transfer Radical Polymerization (ATRP), Stable Free Radical Polymerization (SFRP), also called Nitroxide-Mediated Polymerization (NMP), and Reversible Addition-Fragmentation chain Transfer Polymerization (RAFT Polymerization). While the examples focus on using ATRP, the present invention may be practiced using other controlled/living radical polymerizations, such as SFRP and RAFT.
SFRP, or more generally nitroxide-mediated polymerization, involves the reversible protection and deprotection of the active chain end by a stable free radical called nitroxide. SFRP was developed by Michael Georges (Georges, M. K.; Veregin, R. P. N.; Kazmaier, P. M.; Hamer, G. K., Macromolecules, 1993, 26, 2987-2988. MacLeod, P. J.; Veregin, R. P. N.; Odell, P. G.; Georges, M. K. ibid. 1997, 30, 2207-2208), and has also been shown to perform in aqueous environments.
RAFT Polymerization, developed by a team led by E. Rizzardo (D. G. Hawthorne, G. Moad, E. Rizzardo, S. H. Thang, Macromolecules, 1999, 32, 5457-5459), has been shown to work well in aqueous environments such as emulsion polymerization as described by S. W. Prescott, M. J. Ballard, R. Rizzardo, R. G. Gilbert, Australian J. Chemistry, 2002, 55, 415. It involves a thio-ester catalyst species that is transferred between active chain ends, and facilitates their slow, controlled growth.
Atom transfer radical polymerization is a controlled/xe2x80x9clivingxe2x80x9d polymerization based on the use of radical polymerization to convert monomer to polymer. Although many polymers have been prepared using other types of living polymerizations, researchers have been striving to develop a living radical polymerization for nearly 40 years. An alternative was sought because other types of living polymerizations are severely limited by many factors: only a small number of monomers can be used, the reactions are sensitive to moisture, and two or more monomers cannot be randomly copolymerized. Radical polymerization, in contrast, can polymerize hundreds of monomers, can copolymerize two or more monomers, and can be performed in water as emulsions or suspensions. Controlled/xe2x80x9clivingxe2x80x9d radical polymerization promised to overcome these limitations and provide a method to maximize the potential of living polymerizations.
The Matyjaszewski research group was the first to develop a controlled/xe2x80x9clivingxe2x80x9d polymerization that used a simple, inexpensive polymerization system. It is capable of polymerizing a wide variety of monomers, is tolerant of trace impurities (water, oxygen, inhibitor), and is readily applicable to industrial processes. The system that was developed was termed atom transfer radical polymerization (ATRP). ATRP is a robust system that has generated much interest among polymer chemists in both industry and academia.
The control of the polymerization afforded by ATRP is a result of the formation of radicals that can grow, but are reversibly deactivated to form dormant species. Reactivation of the dormant species allows for the polymer chains to grow again, only to be deactivated later. Such a process results in a polymer chain that slowly, but steadily, grows and has a well-defined end group. For ATRP, that end group is usually an alkyl halide.
The initiator is generally a simple, commercially available, alkyl halide. The catalyst is a transition metal that is complexed by one or more ligands; the catalyst does not need to be used in a one-to-one ratio with the initiator but can be used in much smaller amounts. The deactivator can be formed in situ, or for better control, a small amount (relative to the catalyst) can be added. Additionally, the catalyst is tolerant of water and trace amounts of oxygen.
Although other controlled radical polymerization systems have been reported by various groups, ATRP remains the most powerful, versatile, simple, and inexpensive. ATRP has been able to polymerize a wide range of monomers including various styrenes, acrylates and methacrylates as well as other monomers such as acrylonitrile, vinyl pyridine, and dienes. ATRP commonly uses simple alkyl halides as initiators and simple transition metals (iron, copper) as the catalysts. These catalysts can be used in very low amounts, whereas, other controlled polymerization systems require the use of expensive reagents in much higher concentrations.
As described herein, the in situ synthesis of an amphiphilic co-polymer has been designed to migrate to the oil-water interface and thereto crosslink and precipitate. The amphiphilic copolymer, poly(methyl methacrylate-co-poly(ethylene glycol monomethyl ether) methacrylate)), was prepared by atom transfer radical polymerization (ATRP) in suspension polymerization conditions. ATRP, being a living radical polymerization (Patten, T. E. et. al., Acc. Chem. Res. 1999, 32, 895-903), (Patten, T. E. et. al., Science 1996, 272, 866-868), ensures that all polymer chains remain active and that the water-soluble co-monomer (poly(ethylene glycol methacrylate)) is incorporated continuously into each polymer chain throughout the suspension polymerization. This is essential to impart the desired amphiphilic nature to the copolymer. ATRP is tolerant to water or other protic solvents and impurities unlike ionic living polymerization methods and proceeds efficiently at temperatures below the boiling point of water making it the method of choice for aqueous suspension polymerizations (Matyjaszewski, K. et. al., Macromol. Symp. 2000, 155, 15-29). In addition, this work opens the possibility of building capsular walls from block and terpolymers in future.
The invention may be used to encapsulate very polar materials such as pharmaceutically active materials, dissolved in a polar solvent such as glyceryl triacetate that is suspended in a hydrophobic continuous phase, wherein the continuous phase could be a linear or cycloaliphatic or aromatic solvent ranging from C5 through C20.
This would permit use of many biocompatible monomers such as hydroxyethylmethacrylate and methacrylamide as wall forming monomers at room temperature, using the very active linear amines based on oligomers of ethyleneimines, ranging from 2 through 50 repeat units of ethylene imine.
Other suitable solvents include diphenyl ether, alkyl acetates, alkyl propionates, alkyl butanoates, alkyl adipates, alkyl benzoates, and alkyl phthalates, in each case with alkyl chains ranging from C1 through C12, aliphatic alcohols ranging from C4 through C12, dialkyl ketones with the sum of both alkyl groups ranging from C4 through C20, and dialkyl ethers with the sum of both alkyl groups ranging from C4 through C20. Additionally, industrially used plastizicers such as acetyl trialkyl citrate, with alkyl chains ranging from C2 through C6 can be used.
In addition to the monomers exemplified and described herein, the novel process of the present invention may be employed using other monomers and reagents as follows:
Hydrophilic Monomers:
Methacrylates: polyethyleneglycol methacrylate (PEGMA), with the number of ethylene glycol units ranging from 1 to 22, and dimethylaminoethylmethacrylate (DMAEMA); as well as the analogous acrylates;
Styrenics: polyethyleneglycol modified styrene, with the number of ethyleneglycol units in the PEO chain ranging from 1 through 20;
Acrylamides: alkyl acrylamides and alkylmethacrylamides, where the alkyl group could have from 1 through 3 carbon atoms, including such acrylamides as N-isopropylacrylamide and N,N-dimethylacrylamide; and
Vinyl ethers: methyl vinyl ether, ethylvinyl ether, polyethyleneglycol vinyl ether (PEGVE), with between 1 and 20, preferably between 1 and 5 ethylene glycol units in the PEG chain.
Hydrophobic Monomers:
Methacrylates: alkyl methacrylates (C1-C12, preferably 1-4 carbons in the alkyl group);
Acrylates: Alkyl acrylates (C1-C12, preferably 1-4 carbons in the alkyl group); and
Styrenics: styrene, optionally carrying one or more substituents such as methyl, ethyl or higher alkyl groups.
Crosslinking Monomers:
Oligoethyleneglycol dimethacrylate, containing between 1 and 10 ethyleneglycol units between the two methacrylate groups, preferable between and 4, most preferably either 1 (EGDMA) or 2 (DEGDMA);
Oligoethyleneglycol diacrylates, containing between 1 and 10 ethyleneglycol units between the two acrylate groups, preferable between and 4, most preferably either 1 (EGDA) or 2 (DEGDA);
Bis-acrylamides, containing either a methylene spacer or an ethylene spacer between the two acrylamide units; and
Divinylbenzene (DVB).
Catalysts:
Bipyridines: alkyl modified, where alkyl is a linear or branched aliphatic group having between 3 and 18 carbons, preferably between 6 and 10 carbons;
Alkyl-2-pyridylmethanimines, where the alkyl group could be a linear or branched chain having between 1 and 10 carbons;
Aryl-2-pyridylmethanimines, where the aryl group could be benzene or a substituted benzene group; and
Other catalysts may be chosed from the classes of 1,10-phenantrolines and Picolyl alkyl amines.
Initiators:
Sulfonyl halides, such as tosyl chloride;
Conventional ATRP initiators such as alkyl-2-halo isobutyrate and alkyl-2-halo propionate, where alkyl is a linear or branched alkyl group having between 1 and 10 carbons, preferably between 2 and 4 carbons; and
Benzyl halides such as 1-phenyl-alkyl halide, where alkyl is a linear of branched alkyl group having between 1 and 10 carbons, preferably between 2 and 6 carbons, and where halo stands for either chlorine or bromine.
One aspect of the invention is that the copolymerization of the alkylmethacrylate or acrylate and the polyalkyleneglycol methacrylate or acrylate, can be carried out initially in a homogeneous solution and to different degrees of conversion or chain length. Subsequently, as crosslinking monomers are added and the reaction mixtures transferred into the suspension polymerization reactor, different morphologies are observed. For example, reaction mixtures transferred at high conversion will result in a more capsular morphology, with dense walls, while reaction mixtures transferred at lower conversion in the initial copolymerization will result in final particles showing more homogeneous distribution of polymer throughout the capsule, as in a matrix particle.
In other words, living/controlled polymerization provides the ability to control the polymer solubility in a given core solvent, by controlling the degree of conversion, and hence the length of the living copolymer chains, at which the crosslinker is added and the polymerization mixture is transferred into the suspension reactor. Thus for a given ratio of the comonomers, applicants are able to modify the morphology via the polymer architecture ie., molecular weight of linear polymer chains on the crosslinked polymer. This morphology in turn can control the release behavior of the active materials inside the capsules.